WO1999028316A1 - Thiophene-sulfonamide compounds - Google Patents

Thiophene-sulfonamide compounds Download PDF

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Publication number
WO1999028316A1
WO1999028316A1 PCT/EP1998/006993 EP9806993W WO9928316A1 WO 1999028316 A1 WO1999028316 A1 WO 1999028316A1 EP 9806993 W EP9806993 W EP 9806993W WO 9928316 A1 WO9928316 A1 WO 9928316A1
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Prior art keywords
phenyl
alkoxy
thiophene
amide
sulfonic acid
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PCT/EP1998/006993
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French (fr)
Inventor
Paolo Pevarello
Mario Varasi
Franco Heidempergher
Salvatore Toma
Carmela Speciale
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Pharmacia & Upjohn S.P.A.
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Priority to JP2000523208A priority Critical patent/JP2001524551A/en
Priority to EP98961128A priority patent/EP1034176A1/en
Priority to AU16661/99A priority patent/AU1666199A/en
Priority to CA002310054A priority patent/CA2310054A1/en
Publication of WO1999028316A1 publication Critical patent/WO1999028316A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel thiophene-sulfonamides, to a process for their preparation, to pharmaceutical compositions containing them and their use in therapy.
  • the compounds of the invention act as inhibitors of kynurenine-3-hydroxylase (KYN-OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN), on the one side, and kynurenic acid (KYNA), on the other side, as shown in Figure 1. (The legend to Figure 1 is to be found on the last page of the experimental part of the specification). KYNA is endowed with neuroprotective properties (J. Neurosci.
  • QUIN is a relatively potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders including Huntington's disease and epilepsy (Life Sci. 1984, 35, 19-32; Nature, 1986, 321. 168-171 ; Science, 1983, 219, 316- 318).
  • each of R, R b and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino ⁇ !
  • R 3 is hydrogen, C,-C 6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, Cp alkoxy, nitro, amino, hydroxy, formyla
  • each of R, R and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino,C ⁇ -C 6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy.
  • the present invention also provides a method of treating a mammal, including humans, in need of a kynurenine-3-hydroxylase enzyme inhibitor, such method comprising administering thereto a therapeutically effective .amount of a thiophene- sulfon-amide compound of formula (I)
  • each of R, R b and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino,C
  • each of R, R,, and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino, ⁇ -C 6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbon
  • R 3 is hydrogen, C r C 6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino.
  • each of R and R 5 which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C,-C 6 alkoxy.
  • the present invention includes within its scope all the possible isomers, stereoisomers. optical isomers and their mixtures and the metabolites and the metabolic precursors (or bioprecursors) of the compounds of formula (I).
  • Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium hydroxydes as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.
  • inorganic bases such as sodium, potassium hydroxydes
  • organic acids e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.
  • the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I). i.e. compounds which have a different to formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
  • pharmaceutically acceptable bioprecursors otherwise known as pro-drugs
  • the alkyl, alkoxy, alkanoylamino and alkoxy-carbonyl groups may be branched or straight chain groups.
  • a C r C 6 alkyl group is preferably a C,-C 4 alkyl group.
  • Representative examples of C,-C 4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl.
  • a C C 6 alkoxy group is preferably a C r C 4 alkoxy group.
  • Representative examples of C,-C 4 alkoxy groups include methoxy, and ethoxy.
  • a C 2 -C 6 alkanoylamino group is preferably an acetylamino or propionylamino group.
  • a C,-C 6 alkoxy-carbonyl group is preferably a C r C 4 alkoxy-carbonyl group typically a C,-C 2 one.
  • a halogen is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine.
  • Preferred examplex of R, R ⁇ and R 2 as unsaturated pentatomic heteromonocyclic rings include pyrrole, furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1 ,2,4-oxadiazole and 1 ,3,4-thiadiazole ring.
  • R 4 and R 5 taken together form a C 6 -C 1 aromatic ring system, it is preferably a phenyl or napththalene ring system, which is thus condensed with the oxazole or thiazole moietv.
  • Preferred compounds of formula (I) are those wherein;
  • X is O or S; each of R, R and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 4 alkyl, C r C alkoxy, C 2 -C 4 alkanoylamino, formylamino, ⁇ -C 4 alkoxy-carbonyl, or a pyrrole, furan, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1 ,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole and
  • R 3 is hydrogen, C r C 4 alkyl, or a benzyl or phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 4 alkyl, C r C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C C 4 alkoxy-carbonyl; each of R 4 and R 5 , which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, formylamino and C r C
  • R 5 taken together form a phenyl or napththyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro. amino, phenyl, benzyl, C r C 4 alkyl, C r C 4 alkoxy, C 2 -C 4 alkanoylamino, formylamino and
  • 5-Thiazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide.
  • 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide;
  • a compound of formula (I) may be converted into another compound of formula(I) by known methods.
  • a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid using, an organic cosolvent such as dioxane, tetrahydro furan at a temperature varying between room temperature and about 100 °C.
  • an organic cosolvent such as dioxane, tetrahydro furan at a temperature varying between room temperature and about 100 °C.
  • an amino group may be converted into a formylamino or a C 2 - C 4 alkanoylamino group, for example by reacting with formic acid or with a suitable C 2 -C 4 alkanoyl -anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C.
  • Y as leaving group is a good leaving group, for example a halogen atom, typically chlorine, iodine, or bromine, in particular chlorine.
  • the reaction between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine or pyridine, in a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide. dichloromethane at a temperature varying between 0 °C and about 100 °C.
  • a base such as triethylamine or pyridine
  • a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide.
  • dichloromethane at a temperature varying between 0 °C and about 100 °C.
  • the reaction can be also carried out without base and solvent at a temperature varying between 100 °C and about 200 °C.
  • the conversion of a compound of formula (I) wherein R 3 is hydrogen in another compound of formula (I) wherein R 3 is as defined above except hydrogen can be carried out, for example, in the presence of a base such as sodium hydride, potassium t-butoxide. potassium carbonate in a solvent such as 1 ,2-dimethoxyethane, dioxane. dimethylformamide, acetone and in the presence of a phase-transfer catalyst such as tetra- n-butylammonium iodide at a temperature ranging from about 0 °C to 100 °C, or in the presence of copper bronze and a base such as potassium carbonate at a temperature varying between 100 °C and about 200 °C.
  • the intermediate compounds (II) and (III) are either commercially available or or can be obtained by known methods.
  • the compounds of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3 -hydroxy kynurenine due to excessive activation of neuro transmission mediated by excitatory amino acid receptors and or oxidative stress.
  • neuropathological processes are neurodegenerative pathologies including, e.g. Huntington's chorea, Alzheimer's disease.
  • a human or animal in need of a kynurenine-3-hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof. The condition of the human or animal can thereby be improved.
  • the efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine - 3-hydroxylase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Biochem. (1992), 205, 257-262", with minor modifications.
  • the assay for kynurenine 3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay.
  • the assay for kynurenine 3-hydroxylase activity was carried out at 37°C for a time of 30 min.
  • the reaction mixture of a total volume of 30 ⁇ l was constituted of 44 ⁇ g of suspended extract, 100 mM Tris ICY buffer pH 8.1, 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM- L-Kynurenine, 0.3 ⁇ Ci L-(3,5 - H)Kynurenine (10 Ci/mmol) and 3 ⁇ l of different concentration of inhibitor solutions.
  • the reaction was terminated by the addition of 300 ⁇ l of 7.5 (W/v) activated charcoal, and centrifuged for 7 min..
  • the dosage level suitable for administration to a mammal, e.g.: to humans, depends on the age, weight, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration e.g. for one representative compound of the invention PNU 191386 may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the invention includes also pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g.
  • a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous. isotonic saline solutions or they may contain as a carrier propylene glycol.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Thiophene-2-sulfonic acid (thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
  • the mixture was stirred under nitrogen at 25°C for 24 h.
  • Capsule each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow: Composition for 500 capsules:
  • This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.
  • a pharmaceutical injectable composition can be manufactured dissolving 50 g of 5- Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules.
  • IDO Indolamineoxigenase
  • KYN-OH Kynurenine-3 -hydroxy lase
  • KYNA Kynurenic acid
  • 3-OHAA 3 -Hydroxy anthranilic acid
  • KYNase Kynureninase
  • KAT Kynurenine amino transferase
  • 3-OH-KYN 3-Hydroxy-kynurenine.

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Abstract

Compounds of formula (I) wherein X is O or S; each of R, R1, and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino, C1-C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl; R3 is hydrogen, C1-C6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstitutedor substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and C1-C6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl; and the pharmaceutically acceptable salts thereof have kynurenine-3-hydroxylase enzyme inhibitory activity.

Description

THIOPHENE-SULFONAMIDE COMPOUNDS
The present invention relates to novel thiophene-sulfonamides, to a process for their preparation, to pharmaceutical compositions containing them and their use in therapy.
The compounds of the invention act as inhibitors of kynurenine-3-hydroxylase (KYN-OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN), on the one side, and kynurenic acid (KYNA), on the other side, as shown in Figure 1. (The legend to Figure 1 is to be found on the last page of the experimental part of the specification). KYNA is endowed with neuroprotective properties (J. Neurosci. 1990, 10, 2965-2973), whereas QUIN is a relatively potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders including Huntington's disease and epilepsy (Life Sci. 1984, 35, 19-32; Nature, 1986, 321. 168-171 ; Science, 1983, 219, 316- 318).
Increased concentrations of QUIN have also been indicated as responsible for neurological disorders accompanying many infections and inflammatory diseases including Acquired Immunodeficiency Syndrome (AIDS) (Ann. Neurol. 1991, 29, 202-209). One of the main strategies aimed at altering the KYNA/QUIN balance blocking 3-OH-KYN and QUIN's production and increasing KYNA production, entails inhibition of the key enzyme of the kynurenine (KYN) pathway, among which KYN-OH is of primary importance. Consequently, there is a need in therapy of compounds able of inhibiting this enzyme. The compounds of the present invention fulfill such a need. Accordingly the present invention the use of a thiophene-sulfonamide compound of formula (I)
Figure imgf000003_0001
(I) wherein X is O or S; each of R, Rb and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino^! -C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; R3 is hydrogen, C,-C6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, Cp alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and C,-C6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C)4 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy- carbonyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as kynurenine-3-hydroxylase enzyme inhibitor. The present invention also provides a thiophene-sulfonamide compound of formula (I)
Figure imgf000004_0001
(I) wherein X is O or S; each of R, R and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino,Cι-C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy. C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and CrC6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-Cι aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C.-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy- carbonyl; or a pharmaceutically acceptable salt thereof for use as a medicament, in particular as kynurenine-3-hydroxylase inhibitor. The present invention also provides a method of treating a mammal, including humans, in need of a kynurenine-3-hydroxylase enzyme inhibitor, such method comprising administering thereto a therapeutically effective .amount of a thiophene- sulfon-amide compound of formula (I)
Figure imgf000005_0001
(I) wherein X is O or S; each of R, Rb and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino,C|-C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and CrC6 alkoxy-carbonyl; each of R and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, Cι-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino , and C,-C6 alkoxy-carbonyl; or R and R5 taken together form a C6-Cι4 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C-.-C6 alkyl, C C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy- carbonyl; or a pharmaceutically acceptable salt thereof. The present invention also provides novel thiophene-sulfonamide compounds of formula
(I)
Figure imgf000005_0002
(I) wherein X is O or S; each of R, R,, and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino,^ -C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy-carbonyl;
R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, C,-C6 alkoxy, nitro, amino, hydroxy, formylamino. C2-C6 alkanoylamino and Cι-C6 alkoxy-carbonyl; each of R and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy. C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro. amino. phenyl. benzyl. C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C(-C6 alkoxy- carbonyl; and the pharmaceutically acceptable salts thereof. The present invention includes within its scope all the possible isomers, stereoisomers. optical isomers and their mixtures and the metabolites and the metabolic precursors (or bioprecursors) of the compounds of formula (I).
Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium hydroxydes as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.
As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I). i.e. compounds which have a different to formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
The alkyl, alkoxy, alkanoylamino and alkoxy-carbonyl groups may be branched or straight chain groups.
A CrC6 alkyl group is preferably a C,-C4 alkyl group. Representative examples of C,-C4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl. A C C6 alkoxy group is preferably a CrC4 alkoxy group. Representative examples of C,-C4 alkoxy groups include methoxy, and ethoxy.
A C2-C6 alkanoylamino group is preferably an acetylamino or propionylamino group. A C,-C6 alkoxy-carbonyl group is preferably a CrC4 alkoxy-carbonyl group typically a C,-C2 one. A halogen is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine.
Preferred examplex of R, R{ and R2 as unsaturated pentatomic heteromonocyclic rings include pyrrole, furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1 ,2,4-oxadiazole and 1 ,3,4-thiadiazole ring. When R4 and R5 taken together form a C6-C1 aromatic ring system, it is preferably a phenyl or napththalene ring system, which is thus condensed with the oxazole or thiazole moietv. Preferred compounds of formula (I) are those wherein;
X is O or S; each of R, R and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC4 alkyl, CrC alkoxy, C2-C4 alkanoylamino, formylamino,^ -C4 alkoxy-carbonyl, or a pyrrole, furan, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1 ,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole and
1,3,4-thiadiazole ring;
R3 is hydrogen, CrC4 alkyl, or a benzyl or phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC4 alkyl, CrC4 alkoxy, nitro, amino, hydroxy, formylamino, C2-C4 alkanoylamino and C C4 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC4 alkyl, C,-C4 alkoxy, C2-C4 alkanoylamino, formylamino and CrC4 alkoxy-carbonyl; or R4
•and R5 taken together form a phenyl or napththyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro. amino, phenyl, benzyl, CrC4 alkyl, CrC4 alkoxy, C2-C4 alkanoylamino, formylamino and
CrC4 alkoxy-carbonyl; and the pharmaceutically acceptable salts thereof.
Examples of preferred compounds of formula (I) are the following:
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide;
5-Oxazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide:
5-Thiazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide. 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzothiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzothiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (fhiazol-2-yl)-amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-phenyl-oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (4-phenyl-thiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-phenyl-thiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
Thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (5-chloro-benzothiazol-2-yl)-amide;
Thiophene-2-sulfonic acid (benzothiazol-2-yl)-amide; Thiophene-2-sulfonic acid (oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (thiazol-2-yl)-amide;
Thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (5-phenyl-oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (4-phenyl-thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (5-phenyl-thiazol-2-yl)-amide;
Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide;
Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4- (3-nitro-phenyl)-oxazol-2-yl]-amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2- yl]-amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2- yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]- amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]- amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-phenyl amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-(5-chloro-benzoxazol-2-yl)-amide; and the pharmaceutically acceptable salts thereof.
The compounds of formula (I) and the salts thereof can be obtained, for instance, by a process comprising:
A) reacting a compound of formula (II)
Figure imgf000008_0001
(II) wherein R, R,, and R2, are as defined above and Y is a leaving group, with a compound of formula (III)
Figure imgf000008_0002
(HI) wherein X, R3, R , and R5 are as indicated above; or
B) converting a compound of formula (I) in which R3 is hydrogen in another compound of formula (I) wherein R3 is as defined above except hydrogen; or if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desired converting a salt of a compound of formula (I) into a free compound of formula (I), .and/or if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers. A compound of formula (I) may be converted into another compound of formula(I) by known methods. For example, in a compound of formula (I) a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid using, an organic cosolvent such as dioxane, tetrahydro furan at a temperature varying between room temperature and about 100 °C. Furthermore, for example, an amino group may be converted into a formylamino or a C2- C4 alkanoylamino group, for example by reacting with formic acid or with a suitable C2-C4 alkanoyl -anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C. In a compound of formula (II) Y as leaving group is a good leaving group, for example a halogen atom, typically chlorine, iodine, or bromine, in particular chlorine. The reaction between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine or pyridine, in a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide. dichloromethane at a temperature varying between 0 °C and about 100 °C. The reaction can be also carried out without base and solvent at a temperature varying between 100 °C and about 200 °C.
The conversion of a compound of formula (I) wherein R3 is hydrogen in another compound of formula (I) wherein R3 is as defined above except hydrogen can be carried out, for example, in the presence of a base such as sodium hydride, potassium t-butoxide. potassium carbonate in a solvent such as 1 ,2-dimethoxyethane, dioxane. dimethylformamide, acetone and in the presence of a phase-transfer catalyst such as tetra- n-butylammonium iodide at a temperature ranging from about 0 °C to 100 °C, or in the presence of copper bronze and a base such as potassium carbonate at a temperature varying between 100 °C and about 200 °C. The intermediate compounds (II) and (III) are either commercially available or or can be obtained by known methods.
Pharmacology
The compounds of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3 -hydroxy kynurenine due to excessive activation of neuro transmission mediated by excitatory amino acid receptors and or oxidative stress. Examples of such neuropathological processes are neurodegenerative pathologies including, e.g. Huntington's chorea, Alzheimer's disease. Parkinson's disease, olivopontocerebellar atrophy, non- Alzheimer's dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrome (AIDS), multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma, and epilepsy. A human or animal in need of a kynurenine-3-hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof. The condition of the human or animal can thereby be improved. The efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine - 3-hydroxylase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Biochem. (1992), 205, 257-262", with minor modifications. The assay for kynurenine 3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay. The assay for kynurenine 3-hydroxylase activity was carried out at 37°C for a time of 30 min. The reaction mixture of a total volume of 30 μl was constituted of 44 μg of suspended extract, 100 mM Tris ICY buffer pH 8.1, 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM- L-Kynurenine, 0.3 μCi L-(3,5 - H)Kynurenine (10 Ci/mmol) and 3 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 300 μl of 7.5 (W/v) activated charcoal, and centrifuged for 7 min..
A 75 μl aliquot of supernatant was transferred to optiplate and 200 μl of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation counter. The obtained results, which have been reported in the following Table 1 , demonstrate the efficacy of a representative compound of the invention: 5-Isoxazol-3-yl-thiophene-2- sulfonic acid (5-chloro-benzoxazol-2-yl)-amide (internal code PNU 191386). Table 1
Figure imgf000010_0001
The dosage level, suitable for administration to a mammal, e.g.: to humans, depends on the age, weight, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration e.g. for one representative compound of the invention PNU 191386 may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion. The invention includes also pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous. isotonic saline solutions or they may contain as a carrier propylene glycol.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The following examples illustrate but do not limit the invention.
Example 1
Preparation of 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)- amide:
5-Isoxazol-3-yl-thiophene-2-sulphonyl chloride (0.5 g; 0.0020 mol) was reacted with 2- Amino-5-chlorobenzoxazole (0.34 g; 0.0020 mol) at 140-150 °C for 30'. After cooling the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and with brine, dried over anhydrous sodium sulphate and evaporated to dryness after filtration. The crude product was purified by silica gel column chromatography (ethyl acetate: cyclohexane 1 :2 as eluant), to give 0.3 g of the desired product as a grey solid (m.p. 209-21 1 °C). C,4H8 ClN3O4S2; required: C= 44.04; H= 2.1 1; N= 1 1.01; found: C= 43.85; H= 2.28; N= 10.65.
Analogously the following products can be prepared:
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid benzoxazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid 5-chloro-benzothiazoI-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid benzothiιazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid ox.azol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid thiazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid 4-phenyl-oxazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid 5-phenyl-oxazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid 4-phenyl-thiazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- ■2-sulfonic acid 5-phenyl-thiazol-2-yl)-amide;
5-Isoxazo 3-yl-thiophene- 2-sulfonic acid 4-(3-nitro-phenyl)-oxazol-2-yl]-amide;
5-Isoxazo 3-yl-thiophene- ■2-sulfonic acid 4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
Thiophene ■2-sulfonic acid (5-chloro-benzox-azol-2-yl)-amide;
Thiophene ■2-sulfonic acid (benzoxazol-2-yl)-amide; Thiophene-2-sulfonic acid (5-chloro- benzothiazol-2-yl)-amide;
Thiophene-2-sulfonic acid (benzothiazol-2-yl)-amide;
Thiophene-2-sulfonic acid (oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (5-phenyl-oxazol-2-yl)-amide;
Thiophene-2-sulfonic acid (4-phenyl-thiazol-2-yl)-amide;
Thiophene-2-sulfonic acid (5-phenyl-thiazol-2-yl)-amide;
Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2- yl]-.amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2- yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]- amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thi.azol-2-yl]-
■amide;
5-Oxazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide;
5-Thiazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide.
Example 2
Preparation of 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)- phenyl amide:
Bromobenzene (0.72 g; 0.0046 mol), and 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5- chloro-benzoχ.azol-2-yl)-amide (1.1 g; 0.0029 mol), copper bronze (0.45 g) and potassium carbonate (0.15 g) were heated at reflux for 12 h. To the cooled mixture water was added and the excess of bromobenzene was removed by steam distillation. The cooled residue was ground with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness after filtration. The crude product was purified by silica gel column chromatagraphy (ethyl acetate: cyclohexane 1 :3 as eluant), to give 0.3 g of the desired product as a grey solid. C20HI2C1N3O4S2; required: C= 52.46; H= 2.64; N= 9.18; found: C= 52.08; H= 2.85; N= 8.89.
Analogously the following products can be prepared: 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzoxazol-2-yl)- phenyl amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzothiazol-2-yl)-phenyl amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzothi.azol-2-yl)-phenyl amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (oxazol-2-yl)-phenyl amide; and 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (thiazol-2-yl)-phenyl .amide. Example 3
Preparation of 5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-(5-chloro-benzoxazol-2- ylVamide;
To a solution of 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)- .amide (2.2g; 0.0058 mol) in 20 ml of acetone, potassium carbonate (2.49 g; 0.018 mol), catalytic tetra-n-butylammonium iodide and benzyl bromide (1.2 g; 0.007 mol) were added.
The mixture was stirred under nitrogen at 25°C for 24 h.
The mixture was diluted with 150 mL of ethyl acetate , washed with brine, dried over anhydrous sodium sulphate and evaporated to dryness after filtration. The crude product was purified by silica gel column chromatography (ethyl acetate: cyclohexane 1 :3 as eluant) to give 1.5 g of the desired product as a grey solid. C2|Hι ClN304S2; required: C= 53.45; H= 2.99; N= 8.90; found: C= 53.08; H= 3.20; N= 8.62.
Analogously the following products can be prepared:
5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-(benzoxazol-2-yl)- amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-( (5-chloro-benzothiazol-2-yl)-amide;
5-Isox.azol-3-yl-thiophene-2-sulfonic acid benzyl-( (benzothiazol-2-yl)-amide;
5-Isox-azol-3-yl-thiophene-2-sulfonic acid benzyl-( (oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-( (thiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid ethyl-(benzoxazol-2-yl)- amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid ethyl -( (5-chloro-benzothiazol-2-yl)-amide;
5-Isox-azol-3-yl-thiophene-2-sulfonic acid ethyl -( (benzothiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid ethyl -( (oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid ethyl -( (thiazol-2-yl)-amide; and
5-Isoxazol-3-yl-thiophene-2-sulfonic acid ethyl-(5-chloro-benzoxazol-2-yl)-amide.
Example 4
Capsule, each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow: Composition for 500 capsules:
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide 25 g
Lactose 80 g
Corn starch 5 g
Magnesium stearate 5 g
This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g. Example 5
Intramuscular injection of 50 mg/mL
A pharmaceutical injectable composition can be manufactured dissolving 50 g of 5- Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules.
Legend to Figure 1
IDO = Indolamineoxigenase;
KYN = Kynurenine;
KYN-OH = Kynurenine-3 -hydroxy lase;
KYNA = Kynurenic acid; 3-OHAA = 3 -Hydroxy anthranilic acid;
KYNase = Kynureninase;
QUIN = Quinolinic acid;
3-HAO = 3-Hydroxy anthranilic acid deoxygenase;
KAT = Kynurenine amino transferase; 3-OH-KYN = 3-Hydroxy-kynurenine.

Claims

1. The use of a compound which is a thiophene-sulfonamide of formula (I)
Figure imgf000015_0001
wherein
X is O or S; each of R, Rb and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino^] -C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C j -C6 alkoxy-carbonyl ;
R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and CrC6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C] aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy- carbonyl; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a kynurenine-3 -hydroxy lase enzyme inhibitor.
2. Use according to claim 1 wherein the medicament is for use in the prevention and/or treatment of a neurodegenerative pathology.
3. Use according to claim 2 wherein the neurodegenerative pathology is selected from Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atropy, non- Alzheimer's dementia, multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal or head trauma and epilepsy.
4. A compound which is a thiophene-sulfonamide of formula (I)
Figure imgf000016_0001
(I) wherein X is O or S; each of R, R and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino,^ -C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl;
R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-C6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and C,-C6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy- carbonyl, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance..
5 A compound as claimed in claim 4 for use as a kynurenine-3 -hydroxy lase inhibitor.
A compound which is a thiophene-sulfonamide of formula (I):
Figure imgf000016_0002
(i) wherein X is O or S; each of R, Rb and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, .amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino,C,-C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy-carbonyl; R3 is hydrogen, CrC6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C alkanoylamino and CrC6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; or R4 and R5 taken together form a C6-C1 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl. benzyl, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C,-C6 alkoxy- carbonyl; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6, wherein, in formula (I), X is O or S; each of R, Rb and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC4 alkyl, CrC4 alkoxy, C2-C4 alkanoylamino, formylamino,Cι-C4 alkoxy-carbonyl, or a pyrrole, furan. oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole and 1,3,4-thiadiazole ring; R3 is hydrogen, C,-C4 alkyl, or a benzyl or phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C C4 alkyl, C,-C4 alkoxy, nitro, amino, hydroxy, formylamino, C2-C4 alkanoylamino and C C4 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C4 alkyl, C C4 alkoxy, C2-C4 alkanoylamino, formylamino and CrC4 alkoxy-carbonyl; or R4 and R5 taken together form a phenyl or napththyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC4 alkyl, C C4 alkoxy, C2-C4 alkanoylamino, formylamino and CrC alkoxy-carbonyl; or a pharmaceutically acceptable salts thereof
8. A compound selected from: 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide; 5-Oxazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide; 5-Thi.azol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide; 5-Isox-azol-3-yl-thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5- chloro-benzothiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzothiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (oxazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (thiazol-2-yl)-amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
5-Isoxazol-3 -y l-thiophene-2-sulfonic acid (5 -phenyl-oxazol-2-y l)-amide ;
5-Isox.azol-3-yl-thiophene-2-sulfonic acid (4-phenyl-thiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-phenyl-thiazol-2-yl)-amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide;
Thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide; Thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide; Thiophene-2-sulfonic acid (5-chloro-benzothiazol-2-yl)-amide; Thiophene-2-sulfonic acid (benzothiazol-2-yl)-amide; Thiophene-2-sulfonic acid (oxazol-2-yl)-amide; Thiophene-2-sulfonic acid (thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide; Thiophene-2-sulfonic acid (5-phenyl-oxazol-2-yl)-amide; Thiophene-2-sulfonic acid (4-phenyl-thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (5-phenyl-thiazol-2-yl)-amide; Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; Thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-oxazol-2-yl]-amide; 4-Amino-thiophene-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide; 4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2- yl]-amide;
4,5-Dimethoxy-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2- yl]-amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]- amide;
4-Amino-thiophene-2-sulfonic acid [4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]- amide; 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-phenyl amide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid benzyl-(5-chloro-benzoxazol-2-yl)-amide; .and the pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition comprising a compound as defined in claim 6, and a pharmaceutically acceptable carrier and/or diluent.
10. A method of treating a mammal, including a human, in need of a kynurenine-3- hydroxylase enzyme inhibitor, such method comprising administering thereto a therapeutically effective amount of a compound which is a thiophene-sulfonamide of formula (I)
Figure imgf000019_0001
(I) wherein X is O or S; each of R, R and R2, which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino,C,-C6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl;
R3 is hydrogen, C,-C6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, CrC6 alkyl, CrC6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and C C6 alkoxy-carbonyl; each of R4 and R5, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and CrC6 alkoxy-carbonyl; or R and R5 taken together form a C6-C14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkanoylamino, formylamino and C C6 alkoxy- carbonyl, or a pharmaceutically acceptable salt thereof.
PCT/EP1998/006993 1997-11-27 1998-10-27 Thiophene-sulfonamide compounds WO1999028316A1 (en)

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JP2004517892A (en) * 2000-12-13 2004-06-17 ワイス Heterocyclic sulfonamide inhibitors of β-amyloid production

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WO1994027979A1 (en) * 1993-05-20 1994-12-08 Immunopharmaceutics, Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
EP0819681A2 (en) * 1996-07-19 1998-01-21 F. Hoffmann-La Roche Ag N-(4-Aryl-thiazol-2-yl)-sulfonamides and their use

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JP2004517892A (en) * 2000-12-13 2004-06-17 ワイス Heterocyclic sulfonamide inhibitors of β-amyloid production
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